The androgen receptor (AR) is a member of the steroid nuclear-receptor superfamily of ligand-dependent transcription factors and is widely distributed among reproductive and nonreproductive tissues, including the prostate and seminal vesicles, male and female genitalia, skin, testis, ovary, cartilage, sebaceous glands, hair follicles, sweat glands, cardiac muscle, skeletal and smooth muscle, gastrointestinal vesicular cells, thyroid follicular cells, adrenal cortex, liver, pineal, and numerous brain cortical and subcortical regions, including spinal motor neurons (Negro-Vilar, A. JCE&M 1999 54(10):3459-62). As with the other members of the steroid receptor family, AR has several functional domains including a DNA binding domain (DBD), and a 261 residue ligand-binding domain (LBD) (Mw=30,245 Da) that contains the androgen binding site, and is responsible for switching on the androgen function. The cDNA and amino acid sequences of human and rat androgen receptors have been described (Proc. Natl. Acad. Sci. U.S.A. 1988 85: 7211-7215).
AR is an important target in multiple areas of drug discovery and patient therapy. In Oncology, for example, inhibitors (antagonists or partial antagonists) of the androgen receptor function are useful for the treatment of androgen dependent prostate cancer while agonists or partial agonists of the AR are applicable to the treatment of breast cancer. For metabolic and endocrine diseases disorders, for example, agonists or partial agonists of the androgen receptor function are useful for the treatment of age-related diseases and conditions of cachexia in several disease states including, but not limited to, AIDS. Functional AR has also been identified in various bone cells and androgen administration has beneficial effects on skeletal development and maintenance in men and women.
Progress of androgen therapy has been limited by the inability to separate desirable androgenic activities from undesirable or dose limiting side effects. However, recent advances in the development of selective estrogen receptor modulators (SERMs), with a great degree of tissue selectivity in targeting the estrogen receptor while eliminating undesired side effects, has resulted in the suggestion of SARMs, selective androgen receptor modulators (Negro-Vilar, A. JCE&M 1999 54(10):3459-62; Reid et al. Investigational New Drugs 1999 17:271-284).
U.S. Pat. No. 6,017,924 discloses non-steroidal compounds characterized as high affinity, high specificity agonists, partial agonists (i.e. partial activators and/or tissue-specific activators) and antagonists for androgen receptors based upon a “cis-trans” or “co-transfection” assays. Non-steroidal compounds characterized as high affinity, high specificity agonists, partial agonists (i.e. partial activators and/or tissue-specific activators) and antagonists for androgen receptors via the “cis-trans” or “co-transfection” assays are also described in WO 01/16108, WO 01/16133, and WO 01/16139. This co-transfection assay (Evans et al. Science 1988 240:889-95) is suggested to provide a method for identifying functional agonists and partial agonists which mimic, or antagonists which inhibit, the effect of native hormones, and quantifying their activity for responsive intracellular receptor proteins.
In addition, hydroxyflutamide, a known AR antagonist in most tissues, has been suggested to function as a selective AR modulator (SARM) for effects on IL-6 production by osteoblasts (Hofbauer et al. J. Bone Miner. Res. 1999 14:1330-1337).
Hydroxyflutamide and Casodex, both known to be full AR antagonists in most tissues, have been shown, in AR-transfected PC3 cells, to activate MAP kinases Erk-1 and Erk-2 in an AR dependent fashion similar to DHT (Peterziel et. al. Oncogene 18, 6322-6329 (1999)).
The compound LGD2226, a non-steroidal AR agonist, has also been characterized as a selective androgen receptor modulator for use in the treatment of androgen-related diseases such as osteoporosis, male hormone replacement, male and female sexual dysfunction and cachexia (SCRIP—World Pharmaceutical New FILED 12 May 2000; WO 01/16108; WO 01/16133; and WO 01/16139).
The compound LG120907, a non-steroidal AR antagonist, has been shown, in rats, to have reduced antagonist effects on the hypothalamic axis and on libido (reproductive rate) as compared to other clinically used AR antagonists, such as Casodex. As such, LG120907 has been characterized as a selective androgen receptor modulator for the treatment of prostate cancer (Wang et. al. Poster # P3-126, Endocrine Society 80th Annual Meeting (1998), Hamann et. al. Presentation # S39-2, Endocrine Society 80th Annual Meeting (1998)).
Recent reports exploring the nogenotropic effects of sex steroid hormones such as DHT and E2 on the AR and ER, clearly show that both receptors regulate functions not specifically involved with transcriptional events (Kousteni et. al., Cell 104, 719-730 (2001)). The antiapoptic effects of ER and AR have been shown to be inducible by ligands that have no effects on transcription. It has also been shown that ligands that have effects on transcription can have no antiapoptotic effect.
SARMs exhibiting a difference-in-kind of the modulation effected in tumors containing the androgen receptor relative to the modulation effected in other, nontumor tissues containing the androgen receptor (especially, antagonist activity in tumors versus agonist activity in other, nonmalignant tissues containing the androgen receptor), have heretofore been neither disclosed nor suggested. The present invention provides SARMs, and methods for identifying and designing such SARMs, which exhibit antagonist activity in hormone-dependent tumors while exhibiting no activity, or more preferably agonist activity, against other nontumor tissues containing the androgen receptor. As described below, these SARMs can be employed, for example, to treat hormone-dependent tumors such as prostate cancer in patients by both inhibiting the growth of the tumor while mitigating side effects such as muscle wasting/cachexia, loss of libido, osteoporosis and gynecomastia. The term “patient” as used herein denotes an animal, preferably a mammal such as a dog, cat, or, most preferably, a human.